Myotonic Dystrophy, Type 1

1. What every clinician should know

Clinical features and incidence

Myotonic dystrophy (dystrophia myotonia, commonly abbreviated DM) is an inherited disorder affecting multiple organ systems. The cardinal features are muscle weakness (especially facial, mouth, throat and distal muscle groups) and myotonia (inability to relax contracted muscles). Muscle pain and stiffness are common. Less consistent, but also common, are gastrointestinal dysfunction (mainly dysphagia), excessive sleepiness and cardiac conduction defects (e.g. bundle branch block or A-V block). Many symptoms worsen with time. Treatment is directed toward relieving symptoms and no curative therapy exists. From a perinatal standpoint, the most important feature is the risk of transmitting a severe congenital form, which carries significant morbidity and mortality rates.

Type 1 myotonic dystrophy (DM1) is also called Steinert disease, occurs in about 1 in 8,000 individuals, and is pan-ethnic although it is most common in individuals of European descent. It is transmitted as an autosomal dominant disorder and is virtually always inherited from an affected parent. Males and females are equally likely to be affected. Age of onset varies, depending on the subtype of DM1: mild, classic, or congenital.

The mutation responsible for DM1 is a trinucleotide repeat, located in the 3'-noncoding region of the DMPK gene, which codes for myotonic dystrophy protein kinase (DMPK). DNA mutation analysis of DMPK is the basis for laboratory confirmation of the disorder and is the gold standard for diagnosis.

Risk factors

Affected females are at risk of transmitting the congenital form of DM1 to offspring as a result of massive expansion of the disease allele. Affected males do not transmit the congenital form. The transmitting mother may be minimally symptomatic (in some cases the mother is asymptomatic and undiagnosed). Congenital myotonic dystrophy (CMD) is the most severe form, and is associated with increased neonatal mortality (up to 25% even when recognized and treated). Affected infants have severe respiratory compromise and generalized weakness. The highest mortality is within the first year of life. Significant facial muscle weakness results in a characteristic tented "fish mouth" appearance. Myotonia is not initially present in the newborn with CMD. Survivors of the neonatal period are at 50-60% risk for neurocognitive disability. Additionally, vision problems and autism spectrum disorders are prevalent. Surviving children typically are able to walk, but do have progressive myopathy leading eventually to mobility impairment and early death.

2. Diagnosis and differential diagnosis

A. Establishing the diagnosis

The manifestations of Classic DM1 change over the course of a patient's lifetime. The multiple organ systems that are affected sometimes overshadow the underlying neuromuscular deficits. However, weakness, muscle pain and myotonia are the most consistent features.

The diagnosis is established by DNA testing. Individuals with DM1 have an abnormal number of the trinucleotide repeat CTG, which is normally found in 5-34 copies in the unaffected population. There is a rough correlation between severity of disease and the number of repeats found. A repeat number over 50 is always associated with disease, although age at diagnosis varies widely. Severe disease is not typically present until the repeat size exceeds 100 (see Table I).

There is overlap of disease manifestations within categories, so providing accurate predictions of disease progression and overall prognosis is challenging. Additionally, somatic mosaicism is known to occur, with mitotic expansion occurring in affected individuals, complicating reliable genotype-phenotype correlations. Premutation alleles occur rarely in the population and are typically found only when investigating family members of affected individuals. Universal carrier screening is not recommended for DM1.

In some instances, a diagnosis of an affected mother is not made until suspicion is raised based on fetal sonographic findings.

Confirmatory gene testing provides the basis for diagnosis and is readily available from commercial genetic laboratories. In the absence of a DM1 mutation, the diagnosis must be re-considered.

The diagnosis is typically made by a neurologist. Family history is very helpful in establishing an index of suspicion for this disorder.

Much of the morbidity associated with this disorder is a result of the extramuscular manifestations, as listed in Table II .

Table II.

Extramuscular Manifestations

Organ system

Manifestations

Gastrointestinal

dysphagia, gastroparesis, constipation

Ocular

cataracts, ptosis

Endocrine

hypogonadism (males), hyperinsulinism

CNS

excessive sleepiness, sleep apnea

Skin

premature balding (males)

Expansion of the unstable repeat size occurs during meiosis and is actually more likely to occur with paternal transmission, although with rare exceptions only mothers transmit an allele that expands into the CMD range. Many transmitting parents are minimally symptomatic and may have escaped recognition until later in adulthood. It is not rare for affected women to be ascertained only after suspicion of CMD in a fetus with the typical signs.

Suspicion for CMD should be heightened in any pregnancy complicated by hydramnios and reduced fetal movement. Affected fetuses also often display bilateral talipes equinovarus (clubfeet). Evaluation of this combination of findings should include an assessment for classic myotonic dystrophy. An easy bedside assessment can be performed by asking the patient to shake hands, resulting in elicitation of grip myotonia. Have the patient grasp the examiner's hand or fingers, and then ask her to quickly release the grip. A delay of several seconds is an indicator for formal evaluation by a neurologist.

B. Differential diagnosis

Type 2 myotonic dystrophy: many features similar to DM1, but with no risk of transmission of a congenital form. Due to tetranucleotide repeat - CCTG - within the CNBP gene. Symptoms are typically later in onset, and not associated with diminished lifespan.

Myotonia congenita: rare condition defined by muscle stiffness that first appears in early childhood or infancy. All skeletal muscles (including ocular and facial) are involved. Stiffness tends to improve with "warmup" period of exercise. Due to mutation in CLCN1 gene.

Periodic paralysis: 2 main types exist that are associated either with hyper- or hypokalemia, the latter being more common. The hypokalemia occurs in conjunction with attacks of paralytic weakness. Attacks last from 1 to several hours. Inherited as autosomal dominant with reduced penetrance.

3. Management

Antepartum

Affected women are at risk for cardiac conduction defects and thus should be evaluated with EKG and cardiology consultation. Overt symptomatology is relatively rare and most patients do not require medical treatment. However, given the potential for multisystem involvement, some patients may be on medications with teratogenic potential. Teratogenic medications commonly used in the management of DM include angiotensin-converting enzyme inhibitors, coumadin (if atrial fibrillation is present) and carbamazepine.

Affected women may have carbohydrate intolerance or overt diabetes, and should be screened for such early in pregnancy. Ophthalmologic evaluation to detect cataract formation should be performed if not done in the previous 2 years. Some reports demonstrate increased rates of upper urinary tract disease (pyelonephritis) and so patients should be screened routinely for asymptomatic bacteriuria.

The key components of prenatal care requiring special investigation for patients with DM1 include:

a. Medication history

b. Cardiology evaluation (EKG, possibly echocardiogram)

c. Early screening for diabetes

d. Ophthalmologic exam (if not recently performed)

e. Urine culture each trimester

f. Genetic counseling/prenatal diagnosis.

As DM1 is inherited as an autosomal dominant disorder, an affected parent has a 50% risk for transmitting the disease-causing allele. A key component of prenatal care for women with DM1 is offering prenatal diagnosis and understanding the risks for congenital myotonic dystrophy (CMD). Formal genetic counseling should be part of prenatal care for at-risk patients. Women with larger repeat sizes are overall at higher risk for expansion of the trinucleotide repeat size into the range that causes CMD as compared to women with smaller repeat lengths.

One study reported an incidence of CMD in offspring inheriting the disease allele from a mother with an allele size smaller than 300 to be about 10%. On the other hand , if the maternal allele is over 300, the risk for transmitting the congenital form is over 60%. Unfortunately, once a woman has a fetus affected with CMD, virtually all subsequent offspring inheriting the DM1 allele will have the congenital form.

Prenatal diagnosis is readily available via mutation analysis using amniotic fluid cells or chorionic villi. Direct PCR-based diagnosis is possible for repeat lengths less than 150, but Southern blotting is required for larger alleles. Prenatal diagnosis should be offered to at-risk couples regardless of which parent is affected because of the potential - albeit small for paternal transmission - for repeat expansion into a more severe phenotype.

In some instances, a smaller disease allele may be transmitted due to contraction of the repeat size, although this phenomenon is more commonly seen if the transmitting parent is male.

Patients with DM1 have higher rates of preterm labor and preterm delivery. Although exceptions exist, most of these complications occur in women whose fetus has congenital DM.

Intrapartum

Little data exist to guide specific intrapartum management. Most patients should be managed similarly to other obstetric patients. However, women with Classic DM1 are reported to have prolonged first and second stages of labor. This phenomenon is likely related to smooth muscle involvement of the overall disease. However, in one large series, the rates of operative deliveries were not significantly higher than in the general population.

Affected patients are at risk for some types of anesthetic complications, and this aspect of intrapartum care requires careful coordination with the the anesthesiology team. Ideally the patient will have received an appropriate evaluation prior to her delivery. Regional anesthesia appears to be safe, but inhalational anesthetics and paralyzing agents should be avoided. Patients receiving opioids - whether administered intravenously or through regional analgesia - must be monitored closely for respiratory depression. Although earlier reports of anesthetic complications in patients with DM1 related an increased risk for malignant hyperthermia, this has been refuted in more recent studies.

Postpartum

Postpartum hemorrhage from uterine atony has been reported to be more frequent in women with myotonic dystrophy, although specific risk figures are difficult to find. A risk of about 10% is an appropriate estimate. Standard management measures should be utilized to control postpartum hemorrhage when it does occur.

Patient who received or are receiving opioid analgesia must be monitored closely. Analgesics ideally should be NSAIDs or acetaminophen. Respiratory muscle weakness and the gastroparesis common in DM1 predispose patients to aspiration and postoperative atelectasis. Delayed-onset apnea has been reported frequently.

Although no specific recommendations exist, maternal muscle weakness may contribute to issues with the provision of neonatal care. Mothers should be provided appropriate support resources to assist with newborn care.

4. Complications

Maternal complications of DM1 during pregnancy are infrequent. However, if a patient has more debilitating disease at the time of conception, her pregnancy course is more likely to be problematic. Most pregnancy complications tend to occur, and are certainly more pronounced, when the fetus is affected with CMD.

In one large series, affected women had 32% incidence of preterm labor before 36 weeks with nearly 20% of all patients delivering before 35 weeks. Hydramnios is reported in 15-20% of pregnancies, but is nearly always associated with CMD, and does not typically appear until the 3rd trimester. Interestingly, high rates of placenta previa have also been reported (nearly 10%). Although variable across different studies, somewhat elevated cesarean delivery rates are reported (35-40%). Early pregnancy loss, ectopic pregnancy and preeclampsia are found in rates similar to the general population.

Congenital DM1 is the most serious of perinatal concerns related to this disorder. Surviving children are likely to have neurocognitive deficits. Brain imaging frequently demonstrates ventricular dilation and cerebral atrophy, which may be demonstrable by sonography later in gestation. In addition, vision problems such as low acuity and astigmatism are common. In the majority of series, most, if not all, pregnancies affected with CMD are terminated when the diagnosis is made at an early gestational age.

5. Prognosis and outcome

Prognosis for DM1 patients as related to pregnancy hinges on the transmission of the disease-causing allele and whether it has expanded into the CMD range. Overall pregnancy does not appear to alter longevity in affected women, but symptoms are commonly said to worsen due to the generalized increase in physiologic demands. No series has related higher rates of maternal mortality. However, these patients are considered high-risk and should be managed as such. Careful monitoring and supportive care are essential elements of the prenatal care for an affected patient. Delivery at a tertiary care center is recommended.

6. What is the evidence for specific management and treatment recommendations

Virtually all treatment recommendations are made based on Level C evidence. No randomized trials of any aspect of perinatal care for women affected with DM1 exist. Nonetheless, useful background information and clinical guidance can be found in the following references.